Immunosuppressive capacity of mesenchymal stem cells correlates with metabolic activity and can be enhanced by valproic acid

Abstract

BackgroundMesenchymal stem cells (MSCs) have entered the clinic as an Advanced Therapy Medicinal Product and are currently evaluated in a wide range of studies for tissue regeneration or in autoimmune disorders. Various efforts have been made to standardize and optimize expansion and manufacturing processes, but until now reliable potency assays for the final MSC product are lacking. Because recent findings suggest superior therapeutic efficacy of freshly administered MSCs in comparison with frozen cells, we sought to correlate the T-cell suppressive capacity of MSCs with their metabolic activity.MethodsHuman MSCs were obtained from patients’ bone fragments and were employed in coculture with peripheral blood mononuclear cells (PBMCs) in an allogeneic T-cell proliferation assay to measure immunosuppressive function. Metabolic activity of MSCs was measured in real time in terms of aerobic glycolysis quantified by the extracellular acidification rate and mitochondrial respiration quantified by the oxygen consumption rate.ResultsWe show that MSC-induced suppression of T-cell proliferation was highly dependent on individual healthy donors’ lymphocytes. Moreover, coculture with PBMCs increased the glycolytic and respiratory activity of MSCs considerably in a PBMC donor-dependent manner. The twofold to threefold enhancement of cell metabolism was accompanied by higher T-cell suppressive capacities of MSCs. The cryoprotectant dimethyl sulfoxide decreased metabolic and immunosuppressive performances of MSCs while valproic acid (VPA) increased their glycolytic, respiratory and T-cell suppressive capacity.ConclusionsFunctional fitness of MSCs can be determined by measuring metabolic activity and can be enhanced by exposure to VPA. Pretesting the increment of metabolic activity upon interaction of donor MSCs with patient T-cells provides a rational approach for an individualized potency assay prior to MSC therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0553-y) contains supplementary material, which is available to authorized users.

Activated Mesenchymal Stromal Cells Process and Present Antigens Regulating Adaptive Immunity

“…Non-activated MSCs are highly glycolytic (41), which has been linked to their immunosuppressive capacity (42), while mitochondrial respiration proved less important to the suppressive functionality of MSCs (41). Our findings point toward a stable metabolic phenotype in terms of mitochondrial respiration and glycolysis after activation of MSCs.…”

Mechanisms underlying the protective effects of mesenchymal stem cell-based therapy

“…Recent studies have shown that the immunosuppressive potency of MSCs is predominantly mediated by key molecules including Rap1 and IDO1 [167,168]. Furthermore, novel strategies including hypoxia preconditioning and chemical pre-treatment can significantly enhance the immunosuppressive potency of MSCs [169,170].…”

Integration of genetic and metabolic features related to sialic acid metabolism distinguishes human breast cell subtypes

“…To provide context for this discovery, the first ~25 years of MGE largely focused on the replacement of natural glycans on the cell surface with their non-natural counterparts with only a few reports [ 39 , 48 ] devoted to examining intracellular metabolism (e.g., flux through the relevant nucleotide sugar biosynthetic pathways). The need to more thoroughly evaluate metabolism in MGE analog-treated cells has become increasingly compelling, however, as metabolic profiling gains increasing promise for diverse purposes ranging from evaluating stem cell pluripotency [ 49 – 51 ], monitoring diabetes [ 52 , 53 ], to characterizing cellular physiology in cancer [ 54 – 56 ]. In an example related to cancer, glycolytic flux and glucose metabolism influenced sialylation in malignant breast cells [ 57 , 58 ], leading us to query whether our high-flux ManNAc analogs could be used to perturb sialic acid biosynthesis in unique, cell type-dependent manners and thereby provide insights into this type of cancer.…”